Early Forms of α-Synuclein Pathology Are Associated with Neuronal Complex I Deficiency in the Substantia Nigra of Individuals with Parkinson's Disease

Biomolecules. 2022 May 25;12(6):747. doi: 10.3390/biom12060747.


Idiopathic Parkinson's disease (iPD) is characterized by degeneration of the dopaminergic substantia nigra pars compacta (SNc), typically in the presence of Lewy pathology (LP) and mitochondrial respiratory complex I (CI) deficiency. LP is driven by α-synuclein aggregation, morphologically evolving from early punctate inclusions to Lewy bodies (LBs). The relationship between α-synuclein aggregation and CI deficiency in iPD is poorly understood. While studies in models suggest they are causally linked, observations in human SNc show that LBs preferentially occur in CI intact neurons. Since LBs are end-results of α-synuclein aggregation, we hypothesized that the relationship between LP and CI deficiency may be better reflected in neurons with early-stage α-synuclein pathology. Using quadruple immunofluorescence in SNc tissue from eight iPD subjects, we assessed the relationship between neuronal CI or CIV deficiency and early or late forms of LP. In agreement with previous findings, we did not observe CI-negative neurons with late LP. In contrast, early LP showed a significant predilection for CI-negative neurons (p = 6.3 × 10-5). CIV deficiency was not associated with LP. Our findings indicate that early α-syn aggregation is associated with CI deficiency in iPD, and suggest a double-hit mechanism, where neurons exhibiting both these pathologies are selectively lost.

Keywords: Lewy-pathology; OXPHOS; mitochondria; respiratory chain; synucleinopathy; α-synuclein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Electron Transport Complex I / deficiency
  • Humans
  • Mitochondrial Diseases
  • Neurons / metabolism
  • Parkinson Disease* / pathology
  • Substantia Nigra / metabolism
  • alpha-Synuclein / metabolism


  • alpha-Synuclein
  • Electron Transport Complex I

Supplementary concepts

  • Mitochondrial complex I deficiency

Grant support

This work is supported by grants from The Research Council of Norway (288164), Bergen Research Foundation (BFS2017REK05) and the Western Norway Regional Health Authority (F-10229-D11661).